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Split Personality

Can an Alzheimer culprit do good in MS?

Ingfei Chen and Emily Willingham

Being two-faced doesn’t usually enhance a reputation, but in the case of beta amyloid, it could. Peptides from this protein are best known as the inflammatory, neurotoxic molecules in Alzheimer disease plaques, but they might show a kinder, gentler side in multiple sclerosis (MS). According to a study in Science Translational Medicine on August 1, beta amyloid—or amyloid beta (Aβ)—can tamp down inflammation in mouse models of demyelinating disease.

Given Aβ’s notoriety as a troublemaker in Alzheimer disease, the findings are making the study investigators and other researchers do a double take. “It’s a very fascinating study and certainly an unexpected effect,” says Kurt Giles, a neuroscientist at the Institute for Neurodegenerative Diseases at the University of California, San Francisco (UCSF). “Sometimes, there are surprises in science.”

The Aβ peptides in question result from enzymatic cleavage of amyloid precursor protein (APP), with each fragment type named for its number of amino acids. Aβ40 and Aβ42, the most common versions, tend to clump into massive aggregates, creating insoluble fibrils that compose the brain plaques characteristic of Alzheimer disease. Soluble oligomers, a different form of the peptides that arises when a few Aβ molecules stick together, are currently the prime suspects for poisoning or indirectly triggering the destruction of neurons in the illness (see “Bad Guys—Aβ Oligomers Live Up to Reputation in Human Studies”). But other researchers long ago observed that APP also crops up in degenerating axons in MS, and a 2008 Nature study led by Stanford University neuroimmunologist Lawrence Steinman found increased amounts of Aβ peptides in MS brain lesions, albeit in far smaller than Alzheimer-type quantities (Ferguson et al., 1997; supplementary material in Han et al., 2008).

This association prompted Steinman and his colleagues to study the effects of Aβ40 and Aβ42 administration in the experimental autoimmune encephalomyelitis (EAE) mouse model of demyelinating disease (see “Animal Arsenal”). “People talk about amyloid beta as a marker of axonal damage,” Steinman says, “so we wanted to know what this might be doing in MS.” To find out, the researchers used four different models of EAE, all of which mimic aspects of MS, such as limb paralysis. The team injected Aβ fragments into the animals’ abdominal cavities and from there, the molecules spread into the peripheral circulation. For several reasons, the investigators predicted that motor problems would worsen or remain unchanged. Aβ might stimulate immune cells, which could migrate into the central nervous system and attack neurons there. In EAE, like in MS, overactive immune cells behave in exactly this way. Furthermore, the Aβ peptides themselves can cross the blood-brain barrier.

Contrary to expectation, Steinman says, “we were really surprised that Aβ made paralysis get better and reduced the pathological hallmarks of inflammation” in the brain. The animals showed a decrease in brain and spinal cord lesions, a reduction in T cells and other lymphocytes infiltrating into the brain, and a decline in inflammatory cytokines in the peripheral blood. As a final test, the investigators blocked APP production by deleting the gene for that protein in mice and then induced EAE in the rodents; the demyelinating symptoms intensified. “When we gave it exogenously, the disease improved, and when we knocked it out, things got worse,” Steinman says.

The findings were so unexpected, Steinman says, that the group’s first reaction was, “It must be a mistake. We must have switched the cages, somebody reversed the cards [labeling the cages], … let’s do it again.” But they got the same outcomes in the second round.

Aβ is “one of the most pathological molecules in the museum of neurological diseases,” Steinman says. However, it isn’t unusual for molecules to have dual, seemingly opposing properties, he adds—like the two-faced god Janus. A famous example is steroids, which are natural hormones that relieve inflammation, but they can lead to obesity and thinning bones when produced in excess, as in Cushing’s disease.

The report raises anew fundamental questions about the normal physiological role of Aβ. The mainstream wisdom has long been that it is mere “junk” with no functional purpose, let alone any beneficial activity, says neuroscientist Robert Moir of Massachusetts General Hospital in Charlestown. Most Alzheimer researchers “will be pretty skeptical” of the Stanford group’s findings, he says, noting that the field has an “almost faith-based belief that Aβ is bad.” Although substantial data back the idea that the peptide is pro-inflammatory, he points out that “nobody’s really looked to see whether it has any anti-inflammatory activities.”

But Moir himself has an unconventional viewpoint: In 2010, he and colleague Rudolph Tanzi proposed that Aβ belongs to a family of antimicrobial proteins (AMPs), which serve as the body’s natural antibiotic molecules and adjust immune defense responses. Their research has identified many characteristics that Aβ shares with an AMP called LL-37, including a beta-pleated sheet structure that tends to assemble into insoluble fibrils; soluble oligomers of LL-37 (a mix of beta sheets and other structures) can also be toxic to cells (see “Prague: Aβ Rehabilitated as an Antimicrobial Protein?”; Soscia et al., 2010). What’s more, LL-37 plays a double role of rousing inflammation in some scenarios and squelching it in others (Nijnik et al., 2009). In that light, the discovery that Aβ appears to reduce inflammation and inhibit T cells is consistent with normal AMP functioning, Moir says—and “fits in rather well” with his and Tanzi’s hypothesis that Aβ is a key part of an innate immune defense that, in Alzheimer disease, goes “into overdrive in response to a perceived, although not necessarily real, challenge.”

Still, Moir says of the Stanford team’s report, “it’s a fairly substantial claim, and big claims need very solid proofs.” The study could be stronger, he notes; for instance, one weakness is that it didn’t include a control experiment to rule out the possibility that any old protein, rather than Aβ molecules specifically, might confer the benefits. The researchers could address this issue by administering a peptide with a scrambled Aβ amino acid sequence. Steinman says his lab has done follow-up experiments with scrambled Aβ control peptides that confirm the original findings.

Steinman doesn’t dispute the notion that Aβ is the villain in Alzheimer disease but proposes that "the two ideas could coexist:” On one hand, “large amounts of amyloid in the brain are real bad for you,” he says. In theory, Aβ might be neurotoxic in multiple sclerosis too—no one knows for sure. On the other hand, based on his new results, Steinman speculates that “amyloid itself chases away an inflammatory response” when it’s in the peripheral blood. “So maybe under certain situations, it could be used for benefit" as a therapy. In MS, there’s not enough Aβ around to calm an overreactive immune system, he says, but boosting quantities of the peptides in the periphery might temper the activity of aggressive immune cells that infiltrate into the central nervous system.

A big question, however, is whether the new study is relevant for people with MS and can be translated into novel therapies. While the findings are intriguing and suggest a unique new treatment approach, observations in EAE don't always hold up in human MS, says Istvan Pirko, a neurologist at the Mayo Clinic in Rochester, Minnesota, in an e-mail. Results from animal models must be verified in the human disease before considered valid, he says.

And given Aβ’s nefarious reputation for glomming together into Alzheimer plaques, the concept of using the peptides as a potential MS drug raises obvious concerns. UCSF’s Giles says it isn’t a good idea, based on mouse models of Alzheimer disease using rodents genetically engineered to overproduce APP: In a study published last month, he and colleagues found that injecting Aβ proteins directly into the brain “can actually induce aggregates” there, he says (see “Aβ Sufficient for Seeding—But Is It a Prion?”). The upshot was similar when another research group inoculated mice with Aβ-rich brain extracts (taken from other mice) even when the injections were delivered into the abdomen, as with the EAE mice at Stanford (see “Peripheral Aβ Seeds CAA and Parenchymal Amyloidosis”; Stöhr et al., 2012; Eisele et al., 2010). “One would assume that there’s certainly a risk of inducing aggregation in the brain from peripheral inoculation [of] amyloid beta,” Giles says.

Steinman’s team did not see any Aβ deposits in the brains of the EAE mice, and he notes that the engineered mice in the Alzheimer models didn’t have normal brains, unlike the animals in his study. But one solution to avoid incurring an aggregation risk could be to borrow a page from vaccines and use only a portion of the molecule to selectively trigger the desired anti-inflammatory benefits. Steinman and his colleagues have been homing in on which domains of the peptides produce the beneficial effect and exploring the mechanisms by which they work. But for now, given Aβ’s bad-guy image, their efforts to develop a therapy for MS patients are focused on another molecule called alphaB-crystallin, which can similarly ameliorate EAE and also self-arranges into sticky beta-pleated sheets (Ousman et al., 2007).

Steinman suspects that in both these proteins, the beta-sheet structures are “acting like a sponge” in binding to and sopping up pro-inflammatory molecules in the blood. In other words, the same sticky nature of Aβ that spurs it to form Alzheimer plaques might also underlie its inflammation-soothing powers, Steinman says—a dichotomy that, if true, would no doubt make Janus smile.

Key open questions

What is the normal physiological function of amyloid beta (Aβ)?

Why are Aβ quantities increased in MS brain lesions?

Can administration of Aβ peptides into the peripheral circulation relieve inflammation in MS patients?

Comments

2 Aug 2012

Jeroen Hoozemans, VU University Medical Center Amsterdam

This is a very interesting paper. The effect Abeta has on the immune system is not simple and depends on a lot of other factors. For example, in AD brain, Abeta deposits are associated with a local inflammatory response marked by increased presence of activated microglia and reactive astrocytes. However, Abeta deposits in the brain can also occur in healthy non-demented people, and these deposits are not associated with an inflammatory response. It appears that amyloid associated proteins like complement factor C1q and serum amyloid P component (SAP) have a strong effect on the immunogenicity of Abeta (Veerhuis et al., 2003, Acta Neuropathol.). Amyloid associated factors could be crucial in the dual role of Abeta.

There are not so many reports that have described the effect of Abeta on the peripheral immune system, and how this could affect AD. There is no conclusive data on how Abeta levels change in blood during the progression of AD. However, there is increasing evidence that changes in peripheral immunity have an effect on the risk of developing AD (Eikelenboom et al., 2012, Alz Res Ther.). In this perspective, investigating the effect of Abeta on the function of the peripheral immune system would be very interesting. In theory, changes in Abeta metabolism (removal, degradation, processing, amyloid associated proteins, folding and aggregation) could alter the immune function and contribute to disease like MS and AD.